Although diabetes mellitus is associated with the development of more atherosclerosis, the reasons for this[unreadable] are not entirely understood. Efforts during the past decade to develop animal models of diabetic[unreadable] macrovascular disease were confounded by the development of hyperlipidemia in many diabetic mice or the[unreadable] failure of hyperglycemia alone to accelerate atherosclerosis. We hypothesized that mice were deficient in a[unreadable] gene required to allow the toxic effects of hyperglycemia on arteries. Mice are relatively deficient in aldose[unreadable] reductase (AR), the enzyme that converts glucose to sorbitol. We discovered that LDL receptor knockout[unreadable] mice (Ldlr-/-) made diabetic with streptozotocin (STZ) treatment have accelerated, atherosclerosis when a[unreadable] transgene expressing human AR (hAR) is present. Moreover, heterozygous Ldlr-/- mice also have greater[unreadable] lesion size with STZ-treatment. This grant proposes to study the relationship between AR expression and[unreadable] murine atherosclerosis. The specfic aims are as follows: Aim 1. To determine the effects of hAR expression[unreadable] on macrovascular disease in diabetic models. Dietary and genetic models of insulin deficiency and insulin[unreadable] resistance will be crossed onto the Ldlr-/- background with and without hAR expression. Aim 2. To assess[unreadable] whether AR over-expression in endothelial cells or macrophages mediates hyperglycemia-induced[unreadable] atherosclerosis. These experiments will employ transplantion of bone marrow and production of new lines of[unreadable] transgenic AR expressing mice. Aim 3. To determine whether AR expression in endothelial cells and/or[unreadable] macrophages affects inflammatory processes in the setting of hyperglycemia. Tissue culture experiments will[unreadable] explore pathways relating hAR expression to inflammation and cellular cholesterol uptake. This information[unreadable] will then be used to study AR effects in vivo. These studies will, we expect, illustrate a genetic intervention[unreadable] that leads to reproducible diabetes-mediated acceleration of atherosclerosis in mice. This is significant[unreadable] because it will provide for a model to study this complication and suggest a therapeutic target for prevention[unreadable] of diabetic macrovascular disease.